The goals of this project are to elucidate the mechanisms of action of tumor viruses and to determine the cellular alterations responsible for naturally occurring malignancies. Topics of present interest include: (1) transforming genes of retroviruses and cancer cells; (2) the biology of endogenous retroviruses; (3) the molecular biology of retrovirus replication and transformation; and (4) the application of knowledge gained from these studies to the search for the causes and mechanisms involved in human neoplastic transformation. During the past year, our investigations have provided important new insights regarding sis and ras oncogenes. Highlights of sis include: elucidation of the v-sis biosynthetic pathway; demonstration that the v-sis gene product shares with PDGF all the biologic properties attributed to the growth factor; demonstration that v-sis transformation requires interaction of its transforming protein with PDGF receptors; assignment of functional domains of the v-sis transforming protein relative to previously defined structural entities; and definition of the human c-sis/PDGF-2 transcriptional unit, including upstream promoter and regulatory signals. Structure-function relationship studies of the ras oncogene product have defined domains of the p21-ras protein and have shown that efficient transformation by p21-ras can occur with reduced in vitro GTPase activity. New dominant transforming genes have been isolated from a human diffuse B-cell lymphoma as well as mouse hepatocarcinomas.